Abstract 6337: Tri-specific CD3 x HER2 x HER2 antibodies in 1:2 format recognizing two different epitopes on HER2 demonstrate selective activity on human cancer cells with high HER2 expression
Authors: Jie Zhang, Xiaoqing Wang, Zhenhao Zhou
Journal: Cancer Research (2023)

Abstract Human epidermal growth factor receptor 2 (HER2) is a membrane tyrosine kinase that was found to be amplified and overexpressed in various human cancers including breast cancer. Monoclonal antibodies targeting HER2 such as trastuzumab and pertuzumab provide good therapeutic benefits in patients with high HER2 expression tumors, however, not all patients respond to the treatment, and many suffer recurrence. There is still a large unmet need for targeted therapies to treat HER2 high expression tumors. T cell engaging antibodies that direct T cells to kill cancer cells by simultaneously binding to CD3 on T cells and tumor-associated antigens (TAA) on cancer cells have emerged as a promising new approach. Such therapeutics are potent, but safe use of them depends on selectivity of the TAA engaged. Though HER2 is highly overexpressed in ~ 20% of breast cancer, expression of HER2 is not restricted to cancer cells and present at low level in normal tissues. The capability of selectively targeting cancer cells over HER2 low expressing normal tissues is critical to the safety of CD3 x HER2 antibodies. It is noteworthy to mention that unlike antibody-drug conjugate (ADC) therapeutics, CD3 x HER2 antibodies might not be a good approach to target HER2 low/neg expression tumors due to the difference in mechanism of action. CMG6A19 is a 150 kD IgG-like tri-specific CD3 x HER2 x HER2 T cell-engaging antibody generated on Chimagen’s TRIAD platform. It is capable of simultaneously recognizing and binding to two different epitopes on HER2 proteins. Multiple human cell lines with different levels of HER2 expression were used as targets in the antibody-mediated hPBMC killing assays in vitro and in vivo, among which SK-BR-3, KPL-4 and BT474 have high HER2 expression as seen in HER2 positive cancers, HT55 and JIMT1 have medium level of HER2 expression, and PC3 and MCF7 have HER2 expression level that is close to in normal tissues. Conventional 1:1 IgG-like CD3 x HER2 bispecific antibodies were used as control. Results showed that CMG6A19 demonstrated higher tumor inhibition effect compared to control antibodies in SK-BR-3/KPL-4/BT474 models, meanwhile remarkably weaker effect in PC3/MCF7 models suggesting better safety in HER2 low expressing tissues. This selectivity of reactivity towards HER2 high expressing cells is likely due to the unique orientation of the antibody which allows better T cell activation when antigen abundance is high. Preliminary preclinical study in cynomolgus monkeys suggested that the antibody was well tolerated in monkeys at the dosage of 20 mpk and had a half-life that is comparable to conventional antibodies. CD3 x HER2 x HER2 tri-specific antibodies selectively showed potent anti-tumor activity on HER2 high expressing cells and good safety on HER2 low expressing cells. Current findings warrant further development in human. Citation Format: Jie Zhang, Xiaoqing Wang, Zhenhao Zhou. Tri-specific CD3 x HER2 x HER2 antibodies in 1:2 format recognizing two different epitopes on HER2 demonstrate selective activity on human cancer cells with high HER2 expression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6337.